Interaction of Tamoxifen's Impact on Overall Net Mortality and Quality of Life

Interaction of Tamoxifen's Impact on Overall Net Mortality and Quality of Life

ABSTRACT: Tamoxifen has well-documented activity in
reducing breast cancer mortality. In addition, it has several secondary
effects that may have an overall impact on long-term survival, and that
are of particular importance in patients surviving the primary breast cancer.
To fully understand the therapeutic role of tamoxifen, it is important
to take into account survival differences related to all conditions known
to be affected by tamoxifen. The purpose of this report is twofold. First,
it provides information on mortality rates for conditions other than primary
breast cancer in patients who survive the primary breast cancer, and the
effect of tamoxifen on these mortality rates. Second, it outlines the principal
side effects of tamoxifen that can affect quality of life and briefly summarizes
their management. [ONCOLOGY 11(Suppl 1):45-48, 1997]

Introduction

The main objective of this article is to describe the effects of adjuvant
tamoxifen (Nolvadex) on overall (net) mortality in patients surviving primary
breast cancer, and in particular, to review the interactive relationship
between the effects of tamoxifen on mortality and its effects on quality
of life. Particular attention is paid to the issue of quality of life and
its management, emphasizing that improvement of quality of life results
in increased compliance, which, in turn, may improve the overall survival
impact of tamoxifen. Quality of life represents an important, but not yet sufficiently explored consequence of tamoxifen therapy. Hence, a thorough
and unbiased quantitative analysis of mortality outcomes is essential,
as mortality reduction may drive parallel efforts to improve quality of
life in order to ensure compliance.

Tamoxifen:
Late Mortality in Breast Cancer Survivors

The estrogen agonistic and antagonistic effects of tamoxifen are well
documented.[2] These actions of tamoxifen produce a range of benefits and
side effects that may alter mortality from other conditions affecting breast
cancer patients treated with tamoxifen. The changes in mortality may occur
in opposing directions and vary in order of magnitude.

Current evidence from several randomized trials demonstrates that tamoxifen
reduces the incidence of contra- lateral breast cancer and decreases cardiovascular
disease incidence and mortality with relative risk (RR) reductions of 0.5-0.8.[3-6]
In contrast, uterine cancer and possibly thromboembolic episodes may result
in excess deaths, with relative risk increases of 2-7.5 (Table
1).[4,7-9]

A recent British Columbia report[1] expressed the long-term impact of
tamoxifen on the overall (net) mortality in breast cancer patients surviving
their primary disease in quantitative terms taking into account all known
tamoxifen- associated conditions that have the potential to affect late
mortality. An attempt was made to integrate age- matched mortality rates
of tamoxifen-associated conditions as they interact, in order to avoid
a potential bias that could result if only one of the conditions was considered.

Our calculations estimated that despite a projected modest increase
in mortality from uterine cancer and thrombo- embolic episodes, there will
be a more substantial mortality reduction due to avoidable deaths from
contralateral breast cancer and cardiovascular events. These calculations
were in addition to tamoxifen's previously confirmed improvement of breast
cancer-specific survival, due to avoidance of locoregional and systemic
relapses from primary breast cancer.

Although recent reports of increases in the incidence of uterine cancer
associated with tamoxifen usage [7,8] have captured the interest of the
scientific community and media, our calculations show that there is only
a moderate excess of deaths from endometrial cancer and that there is a
more substantial reduction in deaths from contralateral breast cancer and
cardiac events. One of the main conclusions of our integrated age-matched
analysis is that the rather modest relative risk reductions for conditions
such as contralateral breast cancer or cardiac events will result in large
absolute numbers of saved lives, because the life-long underlying mortality
rates for these conditions are high. On the other hand, using even very
high relative risk increases for conditions such as uterine cancer or thromboembolic
episodes results in a lower absolute number of excess deaths, because the
underlying population mortality rates for these conditions are low.

Because the mortality effects of different conditions are exerted in
opposite directions, the overall picture of tamoxifen's impact on long-term
survival could be skewed if analyses are restricted to only one condition
at a time. Thus, our methodology and results emphasize that only an integrated,
age-matched analysis that captures all conditions simultaneously will have
the potential to present an overall mortality picture and take into consideration
all treatment-affected conditions. With this type of approach, the frequently
observed unintentional or intentional reporting bias could be reduced or
avoided.

Tamoxifen
and Quality of Life: General Comments

While fear of uterine cancer is the most frequently cited reason for
the reluctance of physicians and patients to consider tamoxifen therapy,
it is the less well quantitated area of quality of life that constitutes
the main problem with tamoxifen compliance. Tamoxifen-associated side effects
range from hot flashes, vaginal dryness, and associated dyspareunia with
reduced libido--the more typically described antiestrogen effects of tamoxifen--to
much less frequently discussed, yet commonly observed complaints, such
as insomnia, depression, ocular irritations, gastrointestinal symptomatology
with nausea, and weight gain.

Although reported frequently in mild forms, the frequency of side effects
of tamoxifen affecting quality of life is less well documented because
quantification of quality of life is hampered by the subjective aspect
of the complaints. The evaluation of quality of life is made more difficult
because most clinicians do not use validated quality-of-life instruments
consistently. Such instuments could provide reasonably objective evidence
for the magnitude of effect on quality of life,[21,22] particularly if
they were used more frequently and prospectively in tamoxifen studies,
with testing of quality of life as a defined objective.

Approaches
Toward Improved Quality of Life

Despite tamoxifen's definitively proven survival benefit, its adverse
effects are sufficiently significant that they are an issue that needs
to be addressed. Of particular importance is evidence that side effects
affecting quality of life, which could be tolerated in patients with advanced
or developed breast cancer, represent a large-scale problem in women who
are otherwise well and who may be considering taking tamoxifen for breast
cancer prevention.

From this perspective, it cannot be overemphasized that while the ultimate
goal of therapy is overall improvement in survival, quality-of-life issues
are of great importance, not only because of their impact on the mental
health of patients, but also because noncompliance due to adverse events
may prevent materialization of the survival gain, which is derived only
if the medication is taken as prescribed. Therefore, if mortality is expected
to decrease significantly, efforts to improve quality of life have to be
escalated in proportion.

Hormone Replacement Therapy

The hot flashes and vaginal dryness, with related dyspareunia, loss
of libido, and loss of energy, seen in a large number of patients taking
tamoxifen, are clearly antiestrogenic effects. Although never tested prospectively,
there is a reasonable expectation that these tamoxifen-associated menopausal
complaints could be ameliorated by hormone replacement therapy (HRT) in
the same fashion as are complaints associated with physiologic menopause.

According to many studies, the relative risk rates for the incidence
of breast cancer in populations of women without breast cancer are only
marginally increased by HRT.[10,11] Because of an associated benefit on
nonbreast cancer events, HRT use has been advocated for routine therapy
of menopausal symptoms or as means to improve overall longevity.[12] For
similar reasons, the use of HRT in breast cancer survivors has been recently
advocated for amelioration of menopausal symptoms resulting from adjuvant
chemotherapy or tamoxifen that affect quality of life.[13,20] The use of
HRT in breast cancer patients is particularly attractive if HRT is used
under the protective umbrella of tamoxifen.[14] Preliminary evidence from
small phase II studies of HRT even without tamoxifen indicates that the
rate of breast cancer metastases may not be adversely affected by the use
of HRT.[15-17] Furthermore, there are reasonable expectations that HRT
use may not only improve quality of life in patients who suffer from adverse
menopausal symptoms, but HRT may add to other protective effects of tamoxifen,
such as effects on lipids or prevention of bone loss as it does in patients
who do not have breast cancer.

On the negative side, thromboembolic episodes may be aggravated, and
endometrial carcinogenesis remains a worrisome issue. Uterine cancer incidence
could be substantially reduced with the use of progesterone-containing
HRT combinations due to the well-documented protective effect of pro- gestins
on the estrogen-mediated increase of endometrial neoplasia.[18]

Because the addition of estrogen or progesterone may interfere with
tamoxifen's effects on breast cancer, only very rigorous testing of their
value in controlled clinical trials will fully confirm their overall benefit
in tamoxifen-treated breast cancer patients. At least one randomized trial[19]
and several proposals for HRT trials in breast cancer patients are presently
under consideration by large centers or groups.[13,14] There has also been
a call for studies to investigate the potential benefits of HRT treatment
on menopausal side effects or quality of life, and also possibly on overall
survival, in breast cancer patients treated with or without tamoxifen.[13,19,20]

Nonhormonal
and Alternative Medicine Approaches

There is limited evidence for improvement of menopausal symptoms using
nonhormonal and unconventional approaches. The best studied agents are
alpha-adrenergic agonists, such as clonidine and lofexidine. (Clonidine
is used in tablet form or as a transdermal patch.) For some patients, beta
blockers such as propranolol have been used and anecdotal reports indicate
a good outcome, although lightheadedness can be a problem. Tibolone is
a steroid, with weak estrogenic, androgenic, and progestogenic activity,
with no known adverse endometrial effects. Bellargal, a combination of
belladonna alkaloids, ergotamine tartrate, and phenobarbital, is associated
with improvement of hot flashes, although sedative effects, dry mouth,
and vasoconstriction are possible side effects. The vitamin/herbal approaches
include such agents as vitamin E, the Oriental or North American root of
ginseng, primrose oil, and Astralagus.

Vitamin E is considered effective by some women, particularly as it
may relieve vaginal dryness. In most health food stores across North America,
capsules or tea of ginseng are now available commercially. Ginseng has
been used in China for centuries as a general, nonspecific stimulant and
aphrodisiac and is also considered to be good for many health conditions,
including menopausal symptoms. Its effect is made more credible by the
fact that ginseng root is a rich source of phytoestrogens.

Phytoestrogens, a class of phytosterols, are substances identified in
plants that exert weak estrogenic effects with less well-documented stimulatory
mitotic activity of pure estrogens. The higher intake of phytoestrogens
in Asia is suspected to represent a common link to not only a lower breast
cancer incidence in Asian countries, but also anecdotally with a reduced
intensity of menopausal symptoms in women from underdeveloped countries.

Primrose is an edible North American plant, and its seeds contain primrose
oil, a nontoxic oil containing gamma-linoleic acid, the source of its alleged
activity, which is considered to be of benefit in alleviating hot flashes.
Astralagus, otherwise known as Huang Qi, is a root of a Chinese plant,
one of the most popular components of Chinese herbal remedies considered
to have multiple health benefits including improvement of hot flashes.

Although these agents are used on a large scale in North America, data
on the efficacy of these nonconventional approaches are strictly limited
to anecdotal reports from individual women, greatly amplified by health
food stores and holistic medicine lobbies. Thus, the issue of appropriate
use of these agents clearly needs clarification and testing in properly
designed controlled studies.

Exercise

Exercise and physical activity, perhaps by increasing serum and tissue
levels of steroids, androgens, or endorphins, as well as by lowering blood
pressure and reducing stress and headaches, may be an important step in
relieving many symptoms of menopause, including side effects of tamoxifen,
and improving quality of life. However, the influence of exercise and the
biochemical processes mediating physical conditioning have been investigated
only marginally, despite the fact that they have been frequently observed
to be of major help in mediating subjective benefits on psychosocial trauma.

Conclusion

This report provides a review of tamoxifen's overall benefits and side
effects, focusing on its impact on late mortality in breast cancer patients
surviving their primary disease and on its interaction with a patient's
quality of life during treatment.

The discussion of tamoxifen's effect on late mortality focused on attempts
to distinguish between individual versus total effects. While the survival
improvement for primary breast cancer has been firmly established, tamoxifen's
full effect on late mortality in breast cancer survivors can be only estimated
from quantitative reports of past tamoxifen trials of adjuvant therapy
for breast cancer patients in which tamoxifen was also shown to affect
the incidence and mortality rates of other conditions.

The evaluation of tamoxifen's effect on total mortality is complex,
as relevant conditions are affected at different times, by different orders
of magnitude, and frequently in opposite directions long after tamoxifen
use. What is emerging, however, is that only an age- matched evaluation
integrating all conditions affected by tamoxifen use will provide a complete
picture of its real effect on overall mortality.

All side effects of tamoxifen, primarily those affecting quality of
life, require prospective studies because their management is emerging
as one of the most important aspects of obtaining higher compliance for
tamoxifen therapy. Maximum survival benefit would be expected in a compliant
population. Prospective testing of hormone replacement therapy is indicated,
as evidence points toward enhanced quality of life and possibly improved
survival compared with tamoxifen alone. The nonconventional approaches,
similar to the entry of any new agents or approaches in oncology, also
require controlled testing, on a scale perhaps even more rigorous than
conventional therapies as their use is already advocated or practiced virtually
without any attempt at outcome analysis.

Because their side effects are generally minimal, the nonconventional
approaches may have the potential to substantially improve quality of life
relating to tamoxifen-associated or unassociated symptoms of menopause.
They may thus contribute, in an unknown magnitude, toward a tamoxifen-mediated
increase in late survival of breast cancer patients or populations of women
using tamoxifen in prevention--a notion too important not to be tested
prospectively.